A major focus of our efforts is on the roles played by the IL-2/IL-2R and IL-15/IL-15R systems in the life and death of T cells and the use of these insights to develop IL-2R and IL-15R directed therapies for leukemia and autoimmune diseases. Previously, we defined the IL-2 receptor subunits, IL-2/IL-15R beta and IL-2R alpha, using the first ever reported anti-cytokine receptor monoclonal antibody (anti-Tac, daclizumab) that was developed in our laboratory. These seminal studies on the IL-2 receptor have culminated in the definition of the IL-2R as an exceptionally valuable target for the therapy of leukemia and for autoimmune diseases. We introduced different forms of IL-2 receptor directed therapy using agents we developed including unmodified murine antibodies to IL-2R alpha (anti-Tac), humanized anti-Tac (daclizumab), Zenapex the first antibody directed toward a cytokine receptor to receive FDA approval and this antibody armed with toxins or beta and alpha-emitting radionuclides. In clinical trials we demonstrated that anti-Tac (daclizumab) provides effective therapy for a subset of patients with HTLV-I associated adult T-cell leukemia (ATL). In a separate clinical trial that included patients with refractory Hodgkins Lymphoma daclizumab armed with 90Y we observed remissions in 63% of trial patients.The study's scientific basis was that most normal cells do not express CD25 whereas it is expressed by some Reed-Sternberg cells and specially by rosetting-polyclonal T cells in lymphomatous masses. Yttrium-90 provides strong beta emissions that kill tumor cells at a distance by crossfire. In the 30 HL patients treated with 90Y-daclizumab there were 6 with progressive disease, 5 with stable disease, 7 with partial responses and 12 with complete responses. Responses were seen in patients whose Reed-Sternberg cells expressed CD25 and among the 25 patients whose neoplastic cells were CD25- provided that associated rosetting-T cells expressed CD25.In conclusion repeated 90Y-daclizumab infusions predominantly directed toward non-malignant T cells rosetting around Reed-Sternberg cells provided effective therapy for select HL patients. In a most critical development, as part of our studies of IL-2 receptor directed therapy for HTLV-I associated ATL, we co-discovered a lymphokine, IL-15, that is required for the development and maintenance of NK-cells as well as CD8 memory phenotype T-cells. IL-15 inhibits AICD and favors the survival of CD8 memory cells and is thereby dedicated to the persistence of immunological memory to invading pathogens. We are evaluating the introduction of IL-15 in the treatment of neoplasia. In preclinical studies we demonstrated that IL-15 transgenic mice in contrast to wild-type mice did not develop the colon carcinoma (MC38) following intravenous introduction of the cancer cells and that MC38 cells transfected with IL-15R alpha no longer formed metastases in wild-type mice. In addition we demonstrated that IL-15 provided effective therapy in the MC38 and CT26 colon carcinoma, B16 melanoma and TRAMP-C2 prostatic carcinoma models. These findings provide the scientific basis for the use of IL-15 in lieu of IL-2 in the treatment of select malignancies and for the incorporation of IL-15 into molecular vaccines for cancer and AIDS. In a seminal observation we demonstrated that IL-15 bound to IL-15R alpha on antigen presenting cells is presented in trans to target NK and CD8 cells that express the other IL-15 receptor subunits beta and gamma. In translation of this observation we have demonstrated that addition of an agonist antibody to CD40 increases IL-15R alpha expression and augments IL-15 efficacy in these murine syngeneic tumor models. Abnormalities of IL-15 and IL-15R alpha expression have been described in inflammatory autoimmune disorders and CD8 leukemia/lymphoma. We identified the IL-2/IL-15R beta subunit (CD122) and demonstrated that the receptor is critically involved in the transpresentation and function of IL-15. We prepared an antibody Hu-Mik-Beta-1 under cGMP (Current Good Manufacturing Practices) that inhibits IL-15 action. A parallel anti-CD122 directed monoclonal antibody, TM-beta-1 inhibits such IL-15 transpresentation in mice. We have utilized TM-beta-1 in a murine model of celiac disease and demonstrated that it reversed all of the clinical and pathological features of this disease. Furthermore, TM-beta-1 was effective in the NOD model of diabetes. These observations provide the scientific basis for the selective targeting of IL-2/IL-15R beta in patients with autoimmune diseases and CD8 leukemia/lymphoma associated with disorders of IL-15/IL-15R. To this end, the humanized Mik-Beta-1 monoclonal antibody (Hu-Mik-Beta-1) has been used in clinical trials involving patients with T-cell large granular lymphocytic leukemia (T-cell LGL) and hematocytopenia as well as in those with the HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), a demyelinating neurological disease. Recently we have developed an ELISA system to measure the concentrations of the private receptor IL-15R alpha that was released into the serum and demonstrated elevated levels in patients with T-cell LGL, type 1 diabetes, and those with refractory celiac disease. These studies provide the scientific basis for the use of Hu-Mik-Beta-1 in the treatment of patients with refractory celiac disease and those who are in the process of developing type 1 diabetes. In certain diseases not only IL-15 but also IL-9 and IL-2 are involved in the pathogenesis. In these cases it is difficult to achieve therapeutic efficacy with an antibody directed toward an individual cytokine or cytokine receptor (e.g., IL-2R). IL-2, IL-9 and IL-15 all utilize the JAK3 signaling molecule, suggesting a therapeutic strategy that involves targeting JAK3. We evaluated the action of the JAK3 inhibitor, CP-690,550 produced by Craig Thomas at the NIH on the cytokine dependent ex vivo proliferation that is characteristic of the peripheral blood mononuclear cells (PBMCs) from select patients with smoldering or chronic subtypes of ATL or those with HAM/TSP whose PBMCs are associated with autocrine/paracrine pathways that involve the production of IL-2, IL-9, IL-15 and their receptors. CP-690,550 inhibited the ex vivo spontaneous proliferation of PBMCs from ATL and HAM/TSP patients by means of 67% and 86% respectively. Furthermore, CP-690,550 inhibited STAT5 phosphorylation in isolated ATL cells ex vivo. Finally an in vivo test of biological activity CP-690,550 treatment of mice with a form of CD8 T-cell IL-15 transgenic leukemia that manifests an autocrine IL-15/IL-15R alpha pathway prolonged the survival duration of these tumor-bearing mice. These studies support further evaluation of the JAK3 inhibitor, CP-690,550 in the treatment of select patients with HTLV-1 associated ATL and HAM/TSP, in those with refractory celiac disease as well as those developing type 1 diabetes where a disorder of the IL-15/IL-15R JAK3 signaling system has been demonstrated. In conclusion the emerging understanding of the IL-2/IL-2R and IL-15/IL15-R systems and their signalling pathway provided by the work of Dr. Waldmann has yielded the scientific basis for the development of more rational immune interventions for cytokine and monoclonal antibody mediated receptor directed therapy, that are of value in the prevention of organ allograft rejection, in the treatment of T-cell mediated autoimmune disorders and in a broad range of leukemia/lymphomas including Hodgkins lymphoma. Furthermore, the co-discovery of IL-15 and its production under cGMP may lead to the development of new IL-15 mediated approaches for the treatment of cancer and as a component of molecular vaccines directed toward cancer or AIDS.